Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs

Koller, Alrun N.; Božilović, Jelena; Engels, Joachim W.; Gohlke, Holger

doi:10.1093/nar/gkp1237

Cited by 35 publications

(27 citation statements)

References 73 publications

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“…)[48,53,76–80]. More ambitious is to try to use simulations for some predictions of new structures, and in extreme cases, to simulate the folding pathways of the molecule.…”

Section: What Can Simulations Tell About G-dna and Other Nucleic Amentioning

confidence: 99%

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

Šponer

Cang

Cheatham

2012

Methods

116

177

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The article reviews the application of biomolecular simulation methods to understand the structure, dynamics and interactions of nucleic acids with a focus on explicit solvent molecular dynamics simulations of guanine quadruplex (G-DNA and G-RNA) molecules. While primarily dealing with these exciting and highly relevant four-stranded systems, where recent and past simulations have provided several interesting results and novel insight into G-DNA structure, the review provides some general perspectives on the applicability of the simulation techniques to nucleic acids.

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“…)[48,53,76–80]. More ambitious is to try to use simulations for some predictions of new structures, and in extreme cases, to simulate the folding pathways of the molecule.…”

Section: What Can Simulations Tell About G-dna and Other Nucleic Amentioning

confidence: 99%

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

Šponer

Cang

Cheatham

2012

Methods

116

177

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“…U:A, 37.8°C; F:A, 27.4°C; To :A, 23.0°C). 17 This observation too leaves open the possibility that F pairing entails a residual H-bonding contribution, although it is also known that F furnishes improved stacking in DNA compared with both T and a benzyl C-nucleoside analog. 18 …”

Section: The Hypothesismentioning

confidence: 99%

The Steric Hypothesis for DNA Replication and Fluorine Hydrogen Bonding Revisited in Light of Structural Data

Egli

2012

Acc. Chem. Res.

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CONSPECTUS In DNA, bases pair in a molecular interaction that is both highly predictable and exquisitely specific. Therefore researchers have generally believed that the insertion of the matching nucleotide opposite a template base by DNA polymerases (pols) required Watson-Crick (W-C) hydrogen bond formation. However pioneering work by Kool and coworkers using hydrophobic base analogs such as the T isostere 2,4-difluorotoluene (F) showed that shape rather than H-bonding served as the primary source of specificity in DNA replication by certain pols. This steric hypothesis for DNA replication has gained popularity, perhaps discouraging further experimental studies to address potential limitations of this new idea. The idea that shape trumps H-bonding in terms of pol selectivity largely hinges on the belief that fluorine is a poor H-bond acceptor. However, the shape complementarity model was embraced in the absence of any detailed structural data for match (F:A) and mismatch pairs (F:G, F:C, F:T) in DNA duplexes or at active sites of pols. Although the F and T nucleosides are roughly isosteric, it is unclear whether F:A and T:A pairs exhibit similar geometries. If the former pair is devoid of H-bonding, it will be notably wider than a T:A pair. Because shape/size and H bonding are intimately related, it may not be possible to separate these two properties. Thus the geometries of an isolated F:A pair in water may differ considerably from an F:A pair embedded in a stretch of duplex DNA, at the tight active site of an A-family replicative pol, or within the spacious active site of a Y-family translesion pol. The shape complementarity model may have more significance for pol accuracy than efficiency: this model appears to be most relevant for replicative pols that use specific residues to probe the identity of the nascent base pair from the minor groove side. However, compared with W-C H-bonds researchers have not fully considered the importance of such interactions that include H-bonds in terms of pol fidelity and the shape complementarity model. This Account revisits the steric hypothesis for DNA replication in light of recent structural data and discusses the role of fluorine as an H-bond acceptor. Over the last five years, crystal structures have emerged for nucleic acid duplexes with F paired opposite to natural bases or located at the active sites of DNA pols. These data permit a more nuanced understanding of the role of shape in DNA replication and the capacity of fluorine to form H-bonds. These studies and additional research involving RNA or other fluorine-containing nucleoside analogs within duplexes indicate that fluorine engages in H-bonding in many cases. Although T and F are isosteric at the nucleoside level, replacement of a natural base by F in pairs often changes their shapes and sizes, and dF in DNA behaves differently from rF in RNA. Similarly, the pairing geometries observed for F and T opposite dATP, dGTP, dTTP or dCTP and their H-bonding patterns at the active site of a replicative pol differ c...

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“…28–31 The classic approach toward this end has been the use of ONs containing ‘universal bases’, 32 which fall into two categories: a) aromatic base analogs without hydrogen-bonding capabilities such as 3-nitropyrrole, 29 5-nitroindole, 33 isocarbostyril 34 or pyrene, 13,35–38 and b) hydrogen-bonding universal bases based on inosine 39–41 or other purine moieties. 42,43 However, development of truly ‘universal’ hybridization probes that do not compromise duplex thermostability has generally proven challenging. 44 …”

Section: Introductionmentioning

confidence: 99%

C2′-Pyrene-Functionalized Triazole-Linked DNA: Universal DNA/RNA Hybridization Probes

Hrdlicka

2011

J. Org. Chem.

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Development of universal hybridization probes, i.e., oligonucleotides displaying identical affinity toward matched and mismatched DNA/RNA targets, has been a longstanding goal due to potential applications as degenerate PCR primers and microarray probes. The classic approach toward this end has been the use of ‘universal bases’ that either are based on aromatic base analogs without hydrogen-bonding capabilities or hydrogen-bonding purine derivatives. However, development of probes that enable truly ‘universal’ hybridization without compromising duplex thermostability has proven challenging. Here we have used the ‘click reaction’ to synthesize four C2′-pyrene-functionalized triazole-linked 2′-deoxyuridine phosphoramidites. We demonstrate that oligodeoxyribonucleotides modified with the corresponding monomers display: a) minimally decreased thermal affinity toward DNA/RNA complements relative to reference strands; b) highly robust universal hybridization characteristics (average differences in thermal denaturation temperatures of matched vs mismatched duplexes are < 1.5 °C); and c) exceptional affinity toward DNA targets containing abasic sites opposite of the modification site (ΔTm up to +25 °C). The latter observation, along with results from absorption and fluorescence spectroscopy, indicates that the pyrene moiety is intercalating into the duplex whereby the opposing nucleotide is pushed into an extrahelical position. These properties render C2′-pyrene-functionalized triazole-linked DNA as promising universal hybridization probes for applications in nucleic acid chemistry and biotechnology.

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Aromatic N versus aromatic F: bioisosterism discovered in RNA base pairing interactions leads to a novel class of universal base analogs

Cited by 35 publications

References 73 publications

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

Molecular dynamics simulations of G-DNA and perspectives on the simulation of nucleic acid structures

The Steric Hypothesis for DNA Replication and Fluorine Hydrogen Bonding Revisited in Light of Structural Data

C2′-Pyrene-Functionalized Triazole-Linked DNA: Universal DNA/RNA Hybridization Probes

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